This project seeks to answer some basic questions concerning the spinal mechanisms of analgesia. The first goal of the studies is to characterize the action of several putative neurotransmitters or nociceptive spinal neurons projecting to the brain. Neurophysiological studies of unit activity of identified spinothalamic projection neurons in anesthetized rats will quantify their responses to thermal stimulation and to a putative primary afferent fiber neurotransmitter, substance P. Subsequent experiments will evaluate the effects of other neurotransmitters (enkephalin analogs and monoamines), opiate analgesics (eg., morphine), heterocyclic antidepressant agents (eg., protryptyline), and their combinations on responses to these stimuli. Behavioral experiments designed to monitor ascending spinal systems in unanesthetized mice using intrathecal injections of these agents will address the behavioral relevance of the neurophysiological data. The second goal of this project is to examine alterations in the spinal pharmacology of the above substances which might accompany opiate tolerance and dependence. Such alterations appear to change the interaction between brain areas activated by opiate and spinal systems affected by opiates. Selected experiments from those described above will be repeated in mice and rats made tolerant to and dependent on opiates. A better understanding of the pharmacological consequences of spinal tolerance/dependence will help us in the design of analgesic combinations with reduced liabilities and of techniques for the moderation of opiate withdrawal. This project is important because it investigates the pharmacology of a system -- the spinothalamic projection system -- which has been clearly identified to be important to human pain perception, but which has not been previously studied pharmacologically.